Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study.

BACKGROUND: Tumor human papillomavirus (HPV) status strongly affects overall survival (OS) of oropharyngeal cancer (OPC) patients. Recently, three groups with different outcomes were identified based on HPV status, smoking history and tumor stage. Our objective was to validate this model using a single-institutional retrospective database. PATIENTS AND METHODS: Patients (n=120) diagnosed with OPC at our institution, treated with concomitant cisplatin plus radiotherapy (RT) (n=64), induction chemotherapy followed by concomitant chemoradiation (n=39) or RT alone (n=17), were stratified in three groups with respect to the risk of death (low 26, intermediate 46 and high 49 patients) according to tumor p16 expression as surrogate of HPV status, pack-years of tobacco smoking and nodal/tumor stage. Group-stratified Kaplan-Meier OS curves were estimated and compared using the log-rank test. RESULTS: The 2-year OS estimates were 100%, 86% and 70%, respectively. The difference between the survival curves was statistically significant (P=0.009). The Harrell's concordance index was 0.70. The calibration plot showed a good concordance between our results and those observed in the original study. CONCLUSIONS: This study validates the risk grouping previously identified. Risk-driven clinical decision making and trial designs will help in better defining the most appropriate treatment in OPC patients.

Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution.

BACKGROUND: To assess changes in survival over time of extremity soft tissue sarcoma (ESTS) patients treated at a single reference institution. PATIENTS AND METHODS: Patients with primary localized adult-type ESTS surgically treated at our institution between 1987 and 2007 were retrospectively reviewed. Patients were categorized into four 5-year groups according to the timing of their first operation. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local recurrence (LR), and distant metastases (DMs) were calculated for each time period. RESULTS: A total of 1094 patients were identified. Median follow-up was 81 months. CCI of SSM and LR were significantly better in period 4 in comparison to periods 1-3 (P < 0.001 for both end points), dropping, respectively, from 15% to 6% and from 23% to 9%. An overall improvement of DMs-free survival at 5 years could be detected in the latter period, as well as a better postmetastasis survival. CONCLUSIONS: Reference institutions for sarcomas may have improved their outcome in the last years. Although biases of retrospective analyses as well as the effect of institutional learning curves need to be discounted, it is possible that optimal exploitation of a series of subtle improvements in sarcoma treatment may make a difference in results currently achievable.

Docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer.

BACKGROUND: This monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein-Barr virus -related locally advanced undifferentiated nasopharyngeal cancer. PATIENTS AND METHODS: We retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, and 5-FU 750 mg/m(2)/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m(2) every 21 days for three cycles. RESULTS: Thirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3-4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3-4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%- to 100%), respectively. CONCLUSIONS: In this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.

Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution.

PURPOSE: To explore the prognostic effect of microscopic marginal status after surgery for extremity soft tissue sarcomas. PATIENTS AND METHODS: We analyzed 911 consecutive patients surgically treated throughout a 20-year span at a single referral center. Six hundred forty-two were first seen with a primary tumor, and 269, with a locally recurrent tumor. All patients underwent macroscopically complete resection. Microscopic marginal status was negative (tumor size > 1 mm) in 748 patients and positive (

Prediction of TP53 status for primary cisplatin, fluorouracil, and leucovorin chemotherapy in ethmoid sinus intestinal-type adenocarcinoma.

PURPOSE: To assess the role of TP53 status in predicting pathologic complete remission after primary chemotherapy in patients with ethmoidal intestinal-type adenocarcinoma (ITAC). PATIENTS AND METHODS: Thirty patients with ethmoidal ITAC enrolled onto a phase II study received chemotherapy with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and radiation. On surgical specimens, absence of viable tumor cells was defined as pathologic complete remission (pCR). TP53 status/p53 function, analyzed on pretreatment biopsies, were retrospectively correlated with pathologic results and patient outcome. RESULTS: Twelve patients achieved a pCR; 18 patients did not (overall response rate, 40%). In patients with wild-type (wt) TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively; in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P < or = .0001). At a median 55-month follow-up, all pCR patients were disease-free; 44% of nonresponding patients experienced relapse (P = .0061). CONCLUSION: The results indicate the existence of two genetic ITAC subgroups, defined by differences in TP53 mutational status or protein functionality, that strongly influence pathologic response to primary chemotherapy and, ultimately, prognosis. PFL seems to be highly effective in terms of pCR and disease-free survival in the presence of a wt or a still-efficient p53 protein, even when encoded by a mutated TP53 gene (eg, early-stop codon mutation), but ineffective in ITACs carrying a disabled p53 protein. Whether this model is extensible to other head and neck cancers needs appropriate investigation.

Quality of surgery and outcome in extra-abdominal aggressive fibromatosis: a series of patients surgically treated at a single institution.

PURPOSE: To explore prognostic factors in surgically treated aggressive fibromatosis (extra-abdominal desmoid tumor). PATIENTS AND METHODS: A total of 203 consecutive patients treated with surgery over a 35-year period at a single referral center were retrospectively reviewed. One hundred twenty-eight were first seen at our institution with primary disease, whereas 75 had a recurrent tumor. All patients underwent macroscopically complete resection. Margins were rated as negative in 146 (97 with primary tumors, 49 with recurrences) and positive in 57 (31 in primary, 26 in recurrences) patients. Median follow-up was 135 months. RESULTS: Patients with primary disease had a better disease-free survival rate than those with recurrence (76% v 59% at 10 years). Presenting with a recurrence was also the strongest predictor of local failure in the multivariate analysis. In patients first treated for primary disease, size and site had prognostic significance, whereas microscopically positive surgical margins did not. In contrast, in patients with recurrence, there was a trend toward better prognosis if margins were negative (although this was not significant at multivariate analysis). CONCLUSION: Presence of microscopic disease does not necessarily affect long-term disease-free survival in patients with primary presentation of extra-abdominal desmoid tumors. Thus, function-sparing surgery may be a reasonable choice when feasible without leaving macroscopic residual disease. In patients with recurrences, positive margins may more clearly affect prognosis, potentially necessitating adjuvant radiation in selected cases.

Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial.

PURPOSE: Adjuvant chemotherapy for soft tissue sarcoma is controversial because previous trials reported conflicting results. The present study was designed with restricted selection criteria and high dose-intensities of the two most active chemotherapeutic agents. PATIENTS AND METHODS: Patients between 18 and 65 years of age with grade 3 to 4 spindle-cell sarcomas (primary diameter > or = 5 cm or any size recurrent tumor) in extremities or girdles were eligible. Stratification was by primary versus recurrent tumors and by tumor diameter greater than or equal to 10 cm versus less than 10 cm. One hundred four patients were randomized, 51 to the control group and 53 to the treatment group (five cycles of 4'-epidoxorubicin 60 mg/m(2) days 1 and 2 and ifosfamide 1.8 g/m(2) days 1 through 5, with hydration, mesna, and granulocyte colony-stimulating factor). RESULTS: After a median follow-up of 59 months, 60 patients had relapsed and 48 died (28 and 20 in the treatment arm and 32 and 28 in the control arm, respectively). The median disease-free survival (DFS) was 48 months in the treatment group and 16 months in the control group (P =.04); and the median overall survival (OS) was 75 months for treated and 46 months for untreated patients (P =.03). For OS, the absolute benefit deriving from chemotherapy was 13% at 2 years and increased to 19% at 4 years (P =.04). CONCLUSION: Intensified adjuvant chemotherapy had a positive impact on the DFS and OS of patients with high-risk extremity soft tissue sarcomas at a median follow-up of 59 months. Therefore, our data favor an intensified treatment in similar cases. Although cure is still difficult to achieve, a significant delay in death is worthwhile, also considering the short duration of treatment and the absence of toxic deaths.

The role of radiotherapy in the management of elderly cancer patients in light of the GROG experience.

60-70% of all cancers will develop in individuals aged 65 and over during this century. Radiation therapy will play a major role in the treatment of cancer, especially in the elderly. The Italian Geriatric Oncology Group (GROG) in 1994 started a number of prospective studies to assess the characteristics of each elderly cancer patient referred to the radiotherapy centers (age, gender, performance status, comorbidity, ADL, family status) and the main features of the tumor in that patient. Based on the obtained results, the role of radiotherapy is underlined and future perspectives are identified.

Causes of failure of curative radiation therapy in 205 early glottic cancers.

A retrospective analysis of the results obtained with curative radiation therapy in a series of 205 patients affected by early glottic cancer treated from 1970 to 1985 at the Florence University and Hospital Departments of Radiotherapy is presented. All patients were staged according to TNM System (UICC 1978) as T1-T2 NO. The overall 5-year local control rates were 88% for T1a, 75% for T1b, and 64 for T2. The main cause of failure was progression or recurrence in T (41/48); five failures were observed in T and N at the same time and two in N. Of these 48 patients, 21 (44%) were salvaged with surgery. After surgical salvage of radiation failures, the 5-year survival rates were 95%, 91%, and 73%, respectively, for T1a, T1b, and T2. The extent of T and the number of subsites involved significantly affected local control. Vocal cord mobility was less important. The incidence of failures and damages was analyzed according to the radiation beam, the size of the irradiated volume, fractionation, and total tumor dose.

Staging and follow-up of nasopharyngeal carcinoma: magnetic resonance imaging versus computerized tomography.

PURPOSE: To compare computerized tomography (CT) and magnetic resonance (MR) in relation to their accuracy in the staging of nasopharyngeal carcinoma (NPC); to compare CT and MR in postirradiation follow-up of NPC. METHODS AND MATERIALS: Staging: From 1985 to 1993, 53 patients affected with NPC were studied with MR and CT. All cases were biopsy-proved epithelial carcinoma. Plain and contrast-enhanced CT scans were performed with third-generation scanners. Magnetic resonance were obtained with 0.5 and 1.5 Tesla units in sagittal, axial, and coronal planes. Computerized tomography was chosen as reference method and findings obtained with MR were compared to those obtained with CT. FOLLOW-UP: From 1985 to 1993, 53 patients irradiated with radical intent were followed up with both CT and MR; 71 examinations were performed in all. The baseline follow-up scan was performed, in general, no sooner than 2 months after the end of radiotherapy. All patients were submitted to unlimited clinical follow-up. RESULTS: Staging: Magnetic resonance showed retropharyngeal adenopathies in 6 of 14 cases in which oropharyngeal involvement had been reported after CT; in 3 other patients, adenopathies were recognized on MR, while primary extent to parapharyngeal space had been diagnosed on CT initially. Infiltration of long muscles of the neck was revealed with MR in 14 cases. On the other hand, CT showed bone invasion in 12 patients vs. 8 on MR. Upstaging to T4 occurred in four cases on the basis of CT; no upstaging occurred after MR. FOLLOW-UP: Findings on CT were uncertain in 10 out of 53 patients, disease recurrence was excluded by MR in nine cases, whereas progressive disease was confirmed in one patient. CONCLUSION: Staging: Our series shows that either CT and MR can provide essential information in the staging of NPC. Magnetic resonance, however, seems to provide the most detailed imaging of soft tissue invasion outside the nasopharynx and of retropharyngeal node involvement. Nonetheless, its limitations in evaluating bone details suggest that CT should be always performed when the status of base of skull is uncertain on MR. General reasons and our data indicate that CT can still be considered a valuable tool in routine NPC staging. Follow up: Magnetic resonance may be the modality of choice because it seems to solve, more often than CT, the problems of differentiation between postradiation changes and recurring tumor, apart from those cases showing subtle bone erosions on initial CT scan.

Computed tomography in nasopharyngeal carcinoma: Part I: T-stage conversion with CT-staging.

Two hundred seventeen consecutive patients were treated with radiotherapy alone, with curative intent, from 1970 to 1985 at the Radiotherapy Unit of the University and Hospital of Florence. The distribution according to T and N staging with polytomography was compared to patients (106 out of 217) who had CT scans done at presentation. T1 cases were less frequent (6.6% vs 27%) in the CT-staged series, whereas T3 showed a higher incidence (30.2% vs 12.6%). The advantages of CT over conventional tomography were quantitated in a subset of 97 patients who underwent both staging procedures. Site-by-site, CT displayed a higher percentage of involvement than polytomography: parapharyngeal spread 18% vs 2%, oropharynx 16% vs 8%, choanae and nasal cavities 28% vs 13%, ethmoid and maxillary sinus 29% vs 13%. Information provided by CT caused a T-stage conversion in 23 out of 97 cases (23%): 4 out of 11 T1, 16 out of 44 T2, 3 out of 16 T3.

Computed tomography in nasopharyngeal carcinoma: Part II: Impact on survival.

Two hundred and seventeen consecutive patients affected by nasopharyngeal carcinoma (NPC) were treated with radiotherapy alone, with curative intent, from 1970 to 1985 at the Radiotherapy Unit of the University and Hospital of Florence. A group (A) of 111 patients staged with conventional clinical and radiological method was compared to a second group (B) of 106 patients who underwent CT staging before treatment. Group B showed better 5-year NED survival and local control; only the differences in local control were significant (p less than 0.01). As to primary control statistically significant differences were observed in T2 and T4 cases. We feel that CT could have contributed to the improvement, probably through a more reliable display of the primary extent and a more adequately planned radiotherapeutic treatment. With CT staging we could not increase our skills in prognostically separating stages according to UICC criteria (1978); in Group B only T2 patients presented significant differences in primary control when compared to T3 and T4 patients. However, a multivariate analysis of prognostic factors showed that nodal involvement, primarily, and histology, secondarily, were the most important factors; T stage showed a minor influence on prognosis.

Hyperfractionated and accelerated radiation therapy in central nervous system tumors (malignant gliomas, pediatric tumors, and brain metastases).

The authors review the main contributions of the international literature concerning the role of hyperfractionation (HF), accelerated fractionation (AF), and accelerated hyperfractionation (AHF) of the dose in radiation therapy (RT) of central nervous system tumors. Basic rationales, clinical results, acute/late toxicity, and current prospectives are summarized in three sections focusing on malignant gliomas, pediatric brainstem tumors, and brain metastases. In supratentorial malignant gliomas the superiority of AHF (0.89 Gy x 3 fractions/day; total dose 61.4 Gy) over conventional fractionation ((CF) total dose 58 Gy) was demonstrated by a randomized trial. However, the gain in median survival time was less than 6 months. No other randomized trials support the preferential choice of non-CF schedules outside clinical trials. Ongoing trials are exploring the role of AHF in combination with chemotherapy, hypoxic cell and radiosensitizing agents. As for pediatric brainstem tumors, there are no data to support the routine use of HF that should be preferably used in an investigative setting. As late sequelae have been reported in the few long-term survivors, patients should be carefully selected. Regarding brain metastases AF RT and AHF RT, with their faster treatment course, may represent a convenient alternative to CF RT for the palliation of brain metastases. In carefully selected patients with solitary brain metastases non-CF RT may be part of aggressive treatment approaches.

Accelerated fractionation in advanced head and neck cancer: results and analysis of late sequelae.

From 1975 to 1985, 161 patients affected by head and neck cancer (58 oropharynx, 67 oral cavity, 36 paranasal sinuses) were treated with radiotherapy using an accelerated fractionation (AF) schedule at the University and Hospital Radiotherapy Departments of Florence. Most cases, classified with U.I.C.C. and A.J.C. TNM (1978) were advanced (137/161 = 85%). Five-year actuarial local control and survival was 38% for the oropharynx, 18% and 20% for the oral cavity, and 38% and 31% for the paranasal sinuses. Results were analysed according to T and N stage as well. Severe late sequelae were evaluated in 53 patients without local disease and with a minimum follow-up of one year: 8 patients developed osteonecrosis; there were 3 cases of trismus, 2 cases of laryngeal oedema, one case of blindness and one case of ophthalmitis.

Prognostic significance of accessory cells and lymphocytes in nasopharyngeal carcinoma.

Forty-five consecutive biopsy specimens of nasopharyngeal carcinoma (NPC) and 10 biopsies of healthy nasopharyngeal mucosa obtained from non-cancer patients were investigated by immunohistochemical methods. Monoclonal (B2, T1) and policlonal antibodies (against S-100 protein and lysozyme) with reference to infiltrating lymphocytes and accessory cells (monocytic/macrophagic and dendritic cells) were used. Variable population densities of dendritic cells (S100+) were demonstrated in 22 out of the 45 cases (49%) of NPC; the distribution of these cells was typically within the cancer nests. Monocytic/macrophagic cells (Lys+) were found along the tumor margins and interspersed among the tumor cells in 14 out of 45 (31%) cases. No significant statistical correlation between density of accessory cells and histological type of NPC (classified according to Micheau criteria) was found. Cases with a moderate to marked density of dendritic and monocytic/macrophagic cells survived longer than those with a slight one (mean survival of 63%, 67% and 29%, 27% respectively). In NPC tissues T-lymphocyte infiltration was prevalent. In contrast, B cells were numerous and T cells rare in normal control tissues. The intensity of T-cell infiltration was significantly high in cases with a marked density of S-100+ cells, according to the ability of these cells to present antigens to sensitized T-cells. This study suggests a prognostic significance for reactive cells infiltrating NPC, which means longer survival for cases associated with marked infiltration density of accessory cells.

Radiotherapy in the aged.

Radiation therapy fulfills all the requirements to be used with curative or palliative intent in nearly every case of cancer in the elderly. Radiotherapy is not associated with acute mortality in older persons and can permit organ and tissue preservation. The modern modalities to deliver radiotherapy treatment permit a large sparing of normal tissues. We need major information on proliferative activity of normal tissues and cancer in the elderly, on results according to stage of tumors, and on acute and late sequelae according to performance status of the patient. It is mandatory to perform prospective studies in order to work out protocols for oncologic treatments and specifically for radiotherapy, to treat adequately an increasing part of population.

Altered fractionation schedules in radiotherapy of head and neck cancer. A review.

The authors review the main contributions of international literature to show the current status in clinical trials on unconventional fractionations of the dose in radiotherapy of head and neck cancers. Several clinical (but only a few randomized) trials have been conducted over the last 15 years using hyperfractionated (HF), accelerated (AF) or mixed (HF-AF) schedules. HF schedules have obtained promising results in terms of local control in comparison with conventional fractionation (CF) of the dose. Improvement in survival was also obtained by the random trials of Pinto and Sanchiz, whereas in EORTC trial no. 22791, the improvement in survival rate was only marginal. A significant increase in local control and, less frequently, in survival has been claimed in several studies using HF-AF. Such data still need to be confirmed by a random study, since EORTC trial 22811 showed superimposable results in comparison with CF. Selection of the most suitable cases for altered fractionation schemes is also being studied in ongoing trials of the EORTC (22851) and RTOG (90-03). As regards acute reactions during and after altered fractionation, they are more severe than after CF. Only pure HF with a dose intensity approximately comparable to CF seems to produce similar acute reactions. Several factors have been found to influence the severity of acute mucosal reactions: interfraction interval, overall treatment time, total dose, and field size. As regards late damage, genuine HF schemes seem to cause roughly equivalent late damage in comparison to CF, whereas high-dose intensity schedules have a higher rate of complications. Interfraction interval, overall treatment time, total dose, fraction size and field size can influence the risk of late sequelae. Before altered fractionations can be considered standard therapy, more data are needed, which should be provided by multicentric randomized trials, some of which are already in progress.

Nonstandard fractionation schedules in radiation therapy of head and neck cancer: a review.

The authors present an updated review of the clinical trials on hyperfractionated and accelerated fractionation schedules in radiotherapy of head and neck cancer. The available results in terms of survival and local control, and acute and late toxicity data are summarized in order to show the current status of this research field. The new breed of fractionation schedules that are on study, designed on the ground of new rationales, are presented as well. Finally, an introductory overview of combination therapy including non standard fractionation radiotherapy associated with chemotherapy is reported.

Randomized trials on altered fractionation in head and neck cancer radiotherapy with conventional fractionation as control arm: another lap to go.

The Authors present a review of randomized trials on non conventional fractionation in head and neck cancer radiotherapy with conventional fractionation as control arm. Hyperfractionation was studied in 5 trials, accelerated hyperfractionation in 4 trials and accelerated fractionation in 3 trials. Furthermore, the reviews of eminent Authors dealing with the above mentioned trials are summarized. In spite of improved local control rate reported with hyperfractionation, non conventional radiotherapy schedules are not yet recommended as routine clinical practice, but all the radiation oncologists are Invited to join trials on this subject.

Endocrine status in 29 patients treated by curative radiation therapy for nasopharyngeal carcinoma.

The basal endocrine status of 29 patients treated with curative radiation therapy for nasopharyngeal carcinoma was assessed; they were disease-free for a minimum of 4 years from the end of treatment. None showed clinical evidence of endocrine disease, and most of them had a substantially normal hormonal blood pattern. A slightly elevated TSH value, suggesting subclinical primary hypothyroidism, was found only in two male patients, which could be ascribed to the radiotherapeutic treatment of the neck. Although we cannot exclude more subtle alterations of hypothalamic-pituitary function, the percentage incidence of endocrine impairment in our patients seems lower than previously reported by other authors.